The invention relates to quinazoline derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-proliferative activity such as anti-cancer activity and are accordingly useful in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said quinazoline derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.
Many of the current treatment regimes for cell proliferation diseases such as psoriasis and cancer utilise compounds which inhibit DNA synthesis. Such compounds are toxic to cells generally but their toxic effect on rapidly dividing cells such as tumour cells can be beneficial. Alternative approaches to anti-proliferative agents which act by mechanisms other than the inhibition of DNA synthesis have the potential to display enhanced selectivity of action.
In recent years it has been discovered that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene i.e. a gene which, on activation, leads to the formation of malignant tumour cells (Bradshaw, Mutagenesis, 1986, 1, 91). Several such oncogenes give rise to the production of peptides which are receptors for growth factors. The growth factor receptor complex subsequently leads to an increase in cell proliferation. It is known, for example, that several oncogenes encode tyrosine kinase enzymes and that certain growth factor receptors are also tyrosine kinase enzymes (Yarden et al., Ann. Rev. Biochem., 1988, 57, 443; Larsen et al. Ann. Reports in Med. Chem. 1989, Chpt. 13).
Receptor tyrosine kinases are important in the transmission of biochemical signals which initiate cell replication. They are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor (EGF) and an intracellular portion which functions as a kinase to phosphorylate tyrosine amino acids in proteins and hence to influence cell proliferation. Various classes of receptor tyrosine kinases are known (Wilks, Advances in Cancer Research, 1993, 60, 43-73) based on families of growth factors which bind to different receptor tyrosine kinases. The classification includes Class I receptor tyrosine kinases comprising the EGF family of receptor tyrosine kinases such as the EGF, transforming growth factor a (TGFxcex1), NEU, erbB, Xmrk, DER and let23 receptors, Class II receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin. IGFI and insulin-related receptor (IRR) receptors and Class III receptor tyrosine kinases comprising the plateletderived growth factor (PDGF) family of receptor tyrosine kinases such as the PDGFxcex1, PDGFxcex2 and colony-stimulating factor 1 (CSF1) receptors. It is known that Class I kinases such as the EGF family of receptor tyrosine kinases are frequently present in common human cancers such as breast cancer (Sainsbury et al., Brit. J. Cancer, 1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21 and Klijn et al., Breast Cancer Res. Treat., 1994, 29, 73), non-small cell lung cancers (NSCLCs) including adenocarcinomas (Cerny et al., Brit. J. Cancer, 1986, 54, 265; Reubi et al., Int. J. Cancer, 1990, 45, 269 and Rusch et al., Cancer Research, 1993, 53, 2379) and squamous cell cancer of the lung (Hendler et al., Cancer Cells, 1989, 7, 347), bladder cancer (Neal et al., Lancet, 1985, 366), oesophageal cancer (Mukaida et al., Cancer, 1991, 68, 142), gastrointestinal cancer such as colon, rectal or stomach cancer (Bolen et al., Oncogene Res., 1987, 1, 149), cancer of the prostate (Visakorpi et al., Histochem. J., 1992, 24, 481), leukaemia (Konaka et al., Cell, 1984, 31, 1035) and ovarian, bronchial or pancreatic cancer (European Patent Specification No. 0400586). As further human tumour tissues are tested for the EGF family of receptor tyrosine kinases it is expected that its widespread prevalance will be established in further cancers such as thyroid and uterine cancer. It is also known that EGF type tyrosine kinase activity is rarely detected in normal cells whereas it is more frequently detectable in malignant cells (Hunter, Cell, 1987, 50, 823). It has been shown more recently (W J Gullick, Brit. Med. Bull., 1991, 47, 87) that EGF receptors which possesses tyrosine kinase activity are overexpressed in many human cancers such as brain, lung squamous cell, bladder, gastric, colorectal, breast, head and neck, oesophageal, gynaecological and thyroid tumours.
Accordingly it has been recognised that an inhibitor of receptor tyrosine kinases should be of value as a selective inhibitor of the growth of mammalian cancer cells (Yaish et al. Science, 1988, 242, 933). Support for this view is provided by the demonstration that erbstatin, an EGF receptor tyrosine kinase inhibitor, specifically attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma which expresses EGF receptor tyrosine kinase but is without effect on the growth of another carcinoma which does not express EGF receptor tyrosine kinase (Toi et al., Eur. J. Cancer Clin. Oncol., 1990, 26, 722). Various derivatives of styrene are also stated to possess tyrosine kinase inhibitory properties (European Patent Application Nos. 0211363, 0304493 and 0322738) and to be of use as anti-tumour agents. The in vivo inhibitory effect of two such styrene derivatives which are EGF receptor tyrosine kinase inhibitors has been demonstrated against the growth of human squamous cell carcinoma inoculated into nude mice (Yoneda et al., Cancer Research, 1991, 51, 4430). Accordingly it has been indicated that Class I receptor tyrosine kinase inhibitors will prove to be useful in the treatment of a variety of human cancers. Various known tyrosine kinase inhibitors are disclosed in a more recent review by T R Burke Jr. (Drugs of the Future, 1992, 17, 119).
EGF type receptor tyrosine kinases have also been implicated in non-malignant proliferative disorders such as psoriasis (Elder et al., Science, 1989, 243, 811). It is therefore expected that inhibitors of EGF type receptor tyrosine kinases will be useful in the treatment of non-malignant diseases of excessive cellular proliferation such as psoriasis (where TGFxcex1 is believed to be the most important growth factor) and benign prostatic hypertrophy (BPH), atherosclerosis and restenosis.
It is known from European Patent Applications Nos. 0520722 and 0566226 and from International Patent Applications WO 95/15758, WO 95/19169, WO 96/09294, WO 96/15118, WO 96/16960 and WO 96/30347 that certain quinazoline derivatives which bear an anilino substituent at the 4-position possess receptor tyrosine kinase inhibitory activity. It is further known from European Patent Application No. 0602851 and from International Patent Application WO 95/23141 that certain quinazoline derivatives which bear an anilino substituent at the 4-position also possess receptor tyrosine kinase inhibitory activity.
It is further known from International Patent Application WO 92/20642 that certain aryl and heteroaryl compounds inhibit EGF and/or PDGF receptor tyrosine kinase. There is the disclosure of certain quinazoline derivatives therein but no mention is made of 4-anilinoquinazoline derivatives.
It is further known from European Patent Application No. 0635507 and from International Patent Applications WO 95/06648, WO 95/19970 and WO 96/29331 that certain tricyclic compounds which comprise a 5- or 6-membered ring fused to the benzo-ring of a quinazoline possess receptor tyrosine kinase inhibitory activity or phosphodiesterase inhibitory activity. It is also known from European Patent Application No. 0635498 that certain quinazoline derivatives which carry an amino group at the 6-position and a halogeno group at the 7-position possess receptor tyrosine kinase inhibitory activity.
The in vitro anti-proliferative effect of a 4-anilinoquinazoline derivative has been disclosed by Fry et al., Science, 1994, 265, 1093. It was stated that the compound 4-(3-bromoanilino)-6,7-dimethoxyquinazoline was a highly potent inhibitor of EGF receptor tyrosine kinase.
The in vivo inhibitory effect of a 4,5-dianilinophthalimide derivative which is an inhibitor of the EGF family of receptor tyrosine kinases has been demonstrated against the growth in BALB/c nude mice of a human epidermoid carcinoma A-431 or of a human ovarian carcinoma SKOV-3 (Buchdunger et al., Proc. Nat. Acad. Sci., 1994, 91, 2334).
It is further disclosed in International Patent Applications WO 96/33977, WO 96/33978, WO 96/33979, WO 96/33980 and WO 96/33981 that certain further quinazoline derivatives which bear an anilino substituent at the 4-position possess receptor tyrosine kinase inhibitory activity.
There is no disclosure in these documents of quinazoline derivatives which bear a heteroaryl moiety attached directly to the 6-position (other than the disclosure in International Patent Application WO 96/16960 of certain 4-anilinoquinazolines which bear a 5- or 9-membered nitrogen-linked heteroaryl moiety at the 6-position) or attached to the 6-position by way of a 1- or 2-atom chain, or of an aryl moiety attached directly to the 6-position or attached to the 6-position by way of a 1- or 2-atom chain [other than the disclosure in European Patent Application No. 0566226 of certain 4-anilinoquinazolines which bear an aryl moiety attached to the 6-position by way of a CONH, NHCH2, CH2NH or SCH2 linking chain (with the aryl moiety attached to the first atom of these 2 atom linking groups, for example the carbon atom within the CONH group)].
We have now found that such compounds possess anti-proliferative properties which are believed to arise from their Class I (EGF type) receptor tyrosine kinase inhibitory activity.
According to the invention there is provided a quinazoline derivative of the formula I 
wherein X1 is a direct link or a group of the formula CO, C(R2)2, CH(OR2), C(R2)2xe2x80x94C(R2)2, C(R2)xe2x95x90C(R2), Cxe2x89xa1C, CH(CN), O, S, SO, SO2, N(R2), CON(R2), SO2N(R2), N(R2)CO, N(R2)SO2, OC(R2)2, SC(R2)2, N(R2)C(R2)2, C(R2)2O, C(R2)2S or C(R2)2N(R2), and each R2 is independently hydrogen or (1-4C)alkyl;
wherein Q1 is phenyl, naphthyl or a 5- or 6-membered heteroaryl moiety containing up to 3 heteroatoms selected from oxygen, nitrogen and sulphur, which heterocyclic moiety is a single ring or is fused to a benzo ring, and Q1 optionally bears up to 3 substituents selected from halogeno, hydroxy, amino, trifluoromethoxy, trifluoromethyl, cyano, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, (1-4C)alkylthio-(2-4C)alkoxy, (1-4C)alkylsulphinyl-(2-4C)alkoxy, (1-4C)alkylsulphonyl-(2-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-[(1-4C)alkyl]amino-(2-4C)alkylamino, pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino, morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino, N-(1-4C)alkyl-halogeno-(2-4C)alkylamino, N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino, N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino, (3-4C)alkynoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino, di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino, pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino, morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of the above-mentioned substituents comprising a CH2 (methylene) group which is not attached to a halogeno, SO or SO2 group or to a N, O or S atom optionally bears on said CH2 group a substituent selected from hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;
wherein m is 1 or 2 and each R1 is independently hydrogen, halogeno, trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl or N,N-di-[(1-4C)alkyl]carbamoyl;
and wherein Q2 is phenyl or a 9- or 10-membered bicyclic heterocyclic moiety containing 1 or 2 nitrogen heteroatoms and optionally containing a further heteroatom selected from oxygen, nitrogen and sulphur, and Q2 optionally bears up to 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl, or Q2 is a group of the formula II 
wherein X2 is a group of the formula CO, C(R3)2, CH(OR3), C(R3)2xe2x80x94C(R3)2, C(R3)xe2x95x90C(R3), Cxe2x89xa1C, CH(CN), O, S, SO, SO2, N(R3), CON(R3), SO2N(R3), N(R3)CO, N(R3)SO2, OC(R3)2, SC(R3)2, C(R3)2O or C(R3)2S wherein each R3 is independently hydrogen or (1-4C)alkyl, Q3 is phenyl or naphthyl or a 5- or 6-membered heteroaryl moiety containing up to 3 heteroatoms selected from oxygen, nitrogen and sulphur, which heteroaryl moiety is a single ring or is fused to a benzo ring, and wherein said phenyl or naphthyl group or heteroaryl moiety optionally bears up to 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl, n is 1, 2 or 3 and each R4 is independently hydrogen, halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino or (2-4C)alkanoylamino;
or a pharmaceutically-acceptable salt thereof;
provided that, when Q1 is optionally-substituted phenyl, X1 is not N(R2)CO, N(R2)SO2, OC(R2)2, N(R2)C(R2)2, C(R2)2S or C(R2)2N(R2); and when X1 is a direct link, Q1 is not a 5- or 9-membered nitrogen-linked heteroaryl moiety containing up to 3 nitrogen heteroatoms.
According to a further aspect of the invention there is provided a quinazoline derivative of the formula I
wherein X1 is a direct link or a group of the formula CO, C(R2)2, CH(OR2), C(R2)2xe2x80x94C(R2)2, C(R2)xe2x95x90C(R2), Cxe2x89xa1C, CH(CN), O, S, SO, SO2, N(R2), CON(R2), SO2N(R2), N(R2)CO, N(R2)SO2, OC(R2)2, SC(R2)2, N(R2)C(R2)2, C(R2)2O, C(R2)2S or C(R2)2N(R2), and each R2 is independently hydrogen or (1-4C)alkyl;
wherein Q1 is a 5- or 6-membered heteroaryl moiety containing up to 3 heteroatoms selected from oxygen, nitrogen and sulphur, which heterocyclic moiety is a single ring or is fused to a benzo ring, and Q1 optionally bears up to 3 substituents selected from halogeno, hydroxy, amino, trifluoromethoxy, trifluoromethyl cyano, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy. (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, (1-4C)alkylthio-(2-4C)alkoxy, (1-4C)alkylsulphinyl-(2-4C)alkoxy, (1-4C)alkylsulphonyl-(2-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-[(1-4C)alkyl]amino-(2-4C)alkylamino, pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino, morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino, N-(1-4C)alkyl-halogeno-(2-4C)alkylamino, N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino, N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino, (3-4C)alkynoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino, di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino, pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino, morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and 4-(1-4C)alkylpiperazin-1-yl -(2-4C)alkanoylamino, and wherein any of the above-mentioned substituents comprising a CH2 (methylene) group which is not attached to a halogeno, SO or SO2 group or to a N, O or S atom optionally bears on said CH2 group a substituent selected from hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;
wherein m is 1 or 2 and each R1 is independently hydrogen, halogeno, trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl or N,N-di-[(1-4C)alkyl]carbamoyl;
and wherein Q2 is phenyl which optionally bears up to 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl;
or a pharmaceutically-acceptable salt thereof; provided that, when X1 is a direct link, Q1 is not a 5- or 9-membered nitrogen-linked heteroaryl moiety containing up to 3 nitrogen heteroatoms.
In this specification the term xe2x80x9calkylxe2x80x9d includes both straight and branched chain alkyl groups but references to individual alkyl groups such as xe2x80x9cpropylxe2x80x9d are specific for the straight chain version only. For example when R1 is a hydroxy-(2-4C)alkoxy group, suitable values for this generic radical include 2-hydroxyethoxy, 2-hydroxypropoxy, 1-hydroxyprop-2-yloxy and 3-hydroxypropoxy. An analogous convention applies to other generic terms.
Within the present invention it is to be understood that a quinazoline derivative of the formula I may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which possesses anti-proliferative activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.
The quinazolines of the formula I are unsubstituted at the 2-position thus it is to be understood that the R1 groups are located only on the benzo portion of the quinazoline ring.
It is also to be understood that certain quinazoline derivatives of the formula I can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess anti-proliferative activity.
Suitable values for the generic radicals referred to above include those set out below.
A suitable value for a substituent on Q1, Q2 or Q3, for a substituent on a CH2 group within a substituent on Q1, or for R1, R2, R3 or R4 when it is halogeno is, for example, fluoro, chloro, bromo or iodo;
when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl or butyl;
when it is (1-4C)alkoxy is, for example, methoxy, ethoxy, propoxy. isopropoxy or butoxy;
when it is (1-4C)alkylamino is, for example, methylamino, ethylamino or propylamino;
when it is di-[(1-4C)alkyl]amino is, for example, dimethylamino, diethylamino, N-ethyl-N-methylamino or dipropylamino;
when it is (2-4C)alkanoylamino is, for example, acetamido, propionamido or butyramido;
when it is (1-4C)alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxcarbonyl or tert-butoxycarbonyl;
when it is N-(1-4C)alkylcarbamoyl is, for example, N-methylcarbamoyl or N-ethylcarbamoyl;
and when it is N,N-di-[(1-4C)alkyl]carbamoyl is, for example, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl.
Suitable values for each substituent which may be present on Q1 include, for example:
for (2-4C)alkenyloxy: vinyloxy and allyloxy;
for (2-4C)alkynyloxy: 2-propynyloxy;
for (1-3C)alkylenedioxy: methylenedioxy, ethylenedioxy and propylenedioxy;
for 4-(1-4C)alkylpiperazin-1-yl: 4-methylpiperazin-1-yl and 4-ethylpiperazin-1-yl;
for amino-(1-4C)alkyl: aminomethyl, 2-aminoethyl and 3-aminopropyl;
for (1-4C)alkylamino-(1-4C)alkyl: methylaminomethyl, 2-methylaminoethyl and 3-methylaninopropyl;
for di-[(1-4C)alkyl]amino-(1-4C)alkyl: dimethylaminoethyl, diethylaminomethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl and 3-dimethylaminopropyl;
for pyrrolidin-1-yl-(1-4C)alkyl: pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl and 3-pyrrolidin-1-ylpropyl;
for piperidino-(1-4C)alkyl: piperidinomethyl, 2-piperidinoethyl and 3-piperidinopropyl;
for morpholino-(1-4C)alkyl: morpholinomethyl, 2-morpholinoethyl and 3-morpholinopropyl;
for piperazin-1-yl-(1-4C)alkyl: piperazin-1-ylmethyl, 2-piperazin-1-ylethyl and 3-piperazin-1-ylpropyl;
for 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl: 4-methylpiperazin-1-ylmethyl, 2-(4-methylpiperazin-1-yl)ethyl and 3-(4-methylpiperazin-1-yl)propyl;
for halogeno-(2-4C)alkoxy: 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 3-fluoropropoxy, 3-chloropropoxy, 2,2,2-trifluoroethoxy, 1,1,2,2,2-pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy and 1,1,2,2,3,3,3-heptafluoropropoxy,
for hydroxy-(2-4C)alkoxy: 2-hydroxyethoxy, 3-hydroxypropoxy and 4-hydroxybutoxy;
for (1-4C)alkoxy-(2-4C)alkoxy: 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy and 3-ethoxypropoxy;
for amino-(2-4C)alkoxy: 2-aminoethoxy and 3-aminopropoxy;
for (1-4C)alkylamino-(2-4C)alkoxy: 2-methylaminoethoxy, 2-ethylaminoethoxy, 2-propylaminoethoxy, 3-methylaminopropoxy and 3-ethylaminopropoxy;
for di-[(1-4C)alkyl]amino-(2-4C)alkoxy: 2-dimethylaminoethoxy, 2-(N-ethyl-N-methylamino)ethoxy, 2-diethylaminoethoxy, 2-dipropylaminoethoxy, 3-dimethylaminopropoxy and 3-diethylaminopropoxy;
for pyrrolidin-1-yl-(2-4C)alkoxy: 2-(pyrrolidin-1-yl)ethoxy and 3-(pyrrolidin-1-yl)propoxy;
for piperidino-(2-4C)alkoxy: 2-piperidinoethoxy and 3-piperidinopropoxy;
for morpholino-(2-4C)alkoxy: 2-morpholinoethoxy and 3-morpholinopropoxy;
for piperazin-1-yl-(2-4C)alkoxy: 2-(piperazin-1-yl)ethoxy and 3-(piperazin-1-yl)propoxy;
for 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy: 2-(4-methylpiperazin-1-yl)ethoxy and 3-(4-methylpiperazin-1-yl)propoxy;
for (1-4C)alkylthio-(2-4C)alkoxy: 2-methylthioethoxy and 3-methylthiopropoxy;
for (1-4C)alkylsulphinyl-(2-4C)-alkoxy: 2-methylsulphinylethoxy and 3-methylsulphinylpropoxy;
for (1-4C)alkylsulphonyl-(2-4C)alkoxy: 2-methylsulphonylethoxy and 3-methylsulphonylpropoxy;
for halogeno-(2-4C)alkylamino: 2-fluoroethylamino, 2-chloroethylamino, 2-bromoethylamino, 3-fluoropropylamino and 3-chloropropylamino;
for hydroxy-(2-4C)alkylamino: 2-hydroxyethylamino, 3-hydroxypropylamino and 4-hydroxybutylamino;
for (1-4C)alkoxy-(2-4C)alkylamino: 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropylamino and 3-ethoxypropylamino;
for amino-(2-4C)alkylamino: 2-aminoethylamino, 3-aminopropylamino and 4-aminobutylamino;
for (1-4C)alkylamino(2-4C)alkylamino: 2-methylaminoethylamino, 2-ethyl-aminoethylamino, 2-propylaminoethylamino, 3-methylaminopropylamino, 3-ethylaminopropylamino and 4-methylaminobutylamino;
for di-[(1-4C)alkyl]amino-(2-4C)alkylamino: 2-dimethylaminoethylamino, 2-(N-ethyl-N-methylamino)ethylamino, 2-diethylaminoethylamino, 2-dipropylaminoethylamino, 3-dimethylaminopropylamino, 3diethylaminopropylamino and 4-dimethylaminobutylamino;
for pyrrolidin-1-yl-(2-4C)alkylamino: 2-(pyrrolidin-1-yl)ethylamino and 3-(pyrrolidin-1-yl)propylamino;
for piperidino-(2-4C)alkylamino: 2-piperidinoethylamino and 3-piperidinopropylamino;
for morpholino2-4C)alkylamino: 2-morpholinoethylamino and 3-morpholinopropylamino;
for piperazin-1-yl-(2-4C)alkylamino: 2-(piperazin-1-yl)ethylamino and 3-(piperazin-1-yl)propylamino;
for 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino: 2-(4-methylpiperazin-1-yl)ethylamino and 3-(4-methylpiperazin-1-yl)propylamino;
for N-(1-4C)alkyl-halogeno-(2-4C)alkylamino: N-(2-chloroethyl)-N-methylamino, N-(2-bromoethyl)-N-methylamino and N-(2-bromoethyl)-N-ethylamino;
for N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino: N-(2-hydroxyethyl)-N-methylamino, N-(3-hydroxypropyl)-N-methylamino and N-ethyl-N-(2-hydroxyethyl)amino;
for N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino: N-methyl-N-(2-methoxyethyl)amino, N-methyl-N-(3-methoxypropyl)amino and N-ethyl-N-(2-methoxyethyl)amino;
for halogeno-(2-4C)alkanoylamino: 2-chloroacetamido, 2-bromoacetamido, 3-chloropropionamido and 3-bromopropionamido;
for hydroxy-(2-4C)alkanoylamino: 2-hydroxyacetamido, 3-hydroxypropionamido and 4-hydroxybutyramido;
for (1-4C)alkoxy-(2-4C)alkanoylamino: 2-methoxyacetamido, 2-ethoxyacetamido, 2-propoxyacetamido, 3-methoxypropionamido, 3-ethoxypropionamido and 4-methoxybutyramido;
for (3-4C)alkenoylamino: acrylamido, methacrylamido, crotonamido and isocrotonamido;
for (34C)alkynoylamino: propiolamido;
for amino-(2-4C)alkanoylamino: 2-aminoacetamido. 2-aminopropionamido and 3-aminopropionamido;
for (1-4C)alkylamino-(2-4C)alkanoylamino: 2-methylaminoacetamido, 2-ethylaminoacetamido, 2-methylaminopropionamido and 3-methylaminopropionamido;
for di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino: 2-dimethylaminoacetamido, 2-diethylaminoacetamido, 2-dimethylaminopropionamido and 3-dimethylaminopropionamido;
for pyrrolidin-1-yl-(2-4C)alkanoylamino: 2-pyrrolidin-1-ylacetamido, 2-pyrrolidin-1-ylpropionamido and 3-pyrrolidin-1-ylpropionamido;
for piperidino-(2-4C)alkanoylamino: 2-piperidinoacetamido, 2-piperidinopropionamido and 3-piperidinopropionamido;
for morpholino-(2-4C)alkanoylamino: 2-morpholinoacetamido, 2-morpholinopropionamido and 3-morpholinopropionamido;
for piperazin-1-yl-(2-4C)alkanoylamino: 2-piperazin-1-ylacetamido, 2-piperazin-1-ylpropionamido and 3-piperazin-1-ylpropionamido;
for 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino: 2-(4-methylpiperazin-1-yl)acetamido, 2-(4-methylpiperazin-1-yl)propionamido and 3-(4-methylpiperazin-1-yl)propionamido.
When there is a (1-3C)alkylenedioxy substituted on Q1, the oxygen atoms thereof occupy adjacent positions on the Q1 ring.
When m is 1 the R1 substituent is preferably located at the 7-position of the quinazoline ring.
Suitable substituents formed when any of the substituents on Q1 comprising a CH2 group which is not attached to a halogeno, SO or SO2 group or to a N, O or S atom bears on said CH2 group a substituent selected from hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino include, for example, substituted (1-4C)alkylamino-(2-4C)alkoxy or di-[(1-4C)alkyl]amino-(2-4C)alkoxy groups, for example hydroxy-(1-4C)alkylamino-(2-4C)alkoxy or hydroxy-di-[(1-4C)alkyl]amino-(2-4C)alkoxy groups such as 3-methylamino-2-hydroxypropoxy and 3-dimethylamino-2-hydroxypropoxy.
A suitable value for Q1 and Q3 when it is a naphthyl group is, for example, 1-naphthyl or 2-naphthyl.
A suitable value for Q1 or Q3 when it is a 5- or 6-membered heteroaryl moiety containing up to 3 heteroatoms selected from oxygen, nitrogen and sulphur, which is a single ring is, for example, furyl, pyrrolyl, thienyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyl or thiadiazoylyl, or which is fused to a benzo ring is, for example, benzofuryl, indolyl, benzothienyl, quinolyl. isoquinolyl, benzoxazolyl, indazolyl, benzimidazolyl, benzothiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl or benzotriazolyl. Said heteroaryl moiety may be attached to X1 and X2 through any available position. The optional substituents on Q1 or Q3 may be located at any available position including on any available nitrogen heteroatom.
A suitable value for Q2 when it is 9- or 10-membered bicyclic heterocyclic moiety containing 1 or 2 nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur is, for example, a benzo-fused heterocyclic moiety such as indolyl, isoindolyl, indolizinyl, 1H-benzimidazolyl, 1H-indazolyl, benzoxazolyl, benzo[c]isoxazolyl, benzo[d]isoxazolyl, benzothiazolyl, benzo[c]isothiazolyl, benzo[d]isothiazolyl, 1H-benzotriazolyl, benzo[c]furazanyl, benzo[c][2,1,3]thiadiazolyl, benzo[d][1,2,3]oxadiazolyl, benzo[d][1,2,3]thiadiazolyl, quinolyl, 1,2-dihydroquinolinyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 4H-1,4-benzoxazinyl or 4H-1,4-benzothiazinyl.
The heterocyclic moiety may be attached through any available position including from either of the two rings of the bicyclic heterocyclic moiety. The heterocyclic moiety may bear a suitable substituent such as a (1-4C)alkyl substituent on an available nitrogen atom.
It is also to be understood that, within the structure of formula I, when X1 is, for example, a group of the formula C(R2)2O, it is the C atom which is attached to the quinazoline ring and the O atom which is attached to Q1. Likewise, when X2 is, for example, a group of the formula N(R3)SO2, it is the N atom which is attached to the phenylene ring and the SO2 group which is attached to Q3. Likewise, when X1 is, for example, a group of the formula CON(R2), it is the CO group which is attached to the quinazoline ring and the N atom which is attached to Q1.
A suitable pharmaceutically-acceptable salt of a quinazoline derivative of the invention is, for example, an acid-addition salt of a quinazoline derivative of the invention which is sufficiently basic, for example, a mono- or di-acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically-acceptable salt of a quinazoline derivative of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
Particular novel compounds of the invention include, for example, quinazoline derivatives of the formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Q1, X1, m, R1 and Q2 has any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention:
(a) X1 is a direct link;
(b) X1 is a group of the formula CO, CH2, CH(OH), CH2CH2, CHxe2x95x90CH, Cxe2x89xa1C, O, S, SO, SO2, NH, CONH, SO2NH, NHCO, NHSO2, OCH2, SCH2, NHCH2, CH2O, CH2S or CH2NH;
(c) X1 is a group of the formula CH2, CH2CH2, O, S, SO, SO2, NH, NHCO, NHSO2, OCH2 or NHCH2;
(d) Q1 is phenyl optionally substituted as defined hereinbefore;
(e) Q1 is a 5- or 6-membered monocyclic heteroaryl moiety containing up to 3 heteroatoms selected from oxygen, nitrogen and sulphur which is optionally substituted as defined hereinbefore;
(f) Q1 is furyl, pyrrolyl, thienyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,3-triazolyl or 1,2,4-triazolyl which is attached from any available position including from a nitrogen atom and which is optionally substituted as defined hereinbefore;
(g) Q1 bears no optional substituents;
(h) Q1 bears 1 or 2 substituents selected from halogeno, hydroxy, amino, trifluoromethoxy, trifluoromethyl, cyano, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino and (2-4C)alkanoylamino;
(i) Q1 bears a substituent selected from amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl and 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl;
(j) m is 1 and R1 is hydrogen;
(k) m is 1 and R1 is (1-4C)alkoxy;
(l) Q2 is phenyl which is optionally substituted as defined hereinbefore;
(m) Q2 is a group of the formula II 
wherein X2 is a group of the formula CO, CH2, CH(OH), S, SO2NH or OCH2, Q3 is phenyl or pyridyl which optionally bears 1 or 2 substituents selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy, n is 1 and R4 is hydrogen, halogeno, (1-4C)alkyl or (1-4C)alkoxy;
(n) Q2 is a group of the formula II wherein X2 is a group of the formula CO, Q3 is phenyl which optionally bears 1 or 2 substituents selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy, n is 1 and R4 is hydrogen, halogeno or (1-4C)alkyl; and
(o) Q2 is a group of the formula 11 wherein X2 is a group of the formula OCH2, Q3 is pyridyl, n is 1 and R4 is hydrogen. halogeno or (1-4C)alkyl; provided that when Q1 is optionally-substituted phenyl, X1 is not N(R2)CO, N(R2)SO2, OC(R2)2, N(R2)C(R2)2, C(R2)2S or C(R2)2N(R2); and when X1 is a direct link, Q1 is not a 5- or 9-membered nitrogen-linked heteroaryl moiety containing up to 3 nitrogen heteroatoms.
A preferred compound of the invention is a quinazoline derivative of the formula I
wherein X1 is a direct link or a group of the formula CH2, CH2CH2, NH, NHCO, NHSO2, OCH2, SCH2, NHCH2, CH2O or CH2S;
Q1 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-oxazolyl, 4-oxazolyl, 5-isoxazolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 2-thiazolyl, 4-thiazolyl, 5-isothiazolyl or 1,2,3-triazol-4-yl which optionally bears a substituent selected from methyl, aminomethyl, 2-aminoethyl, methylaminomethyl, 2-methylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, piperidinomethyl, 2-piperidinoethyl, morpholinomethyl, 2-morpholinoethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl, 4-methylpiperazin-1-ylmethyl and 2-(4-methylpiperazin-1-yl)ethyl;
m is 1 and R1 is hydrogen or methoxy;
and Q2 is phenyl which optionally bears 1, 2 or 3 substituents selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl and methoxy,
or Q2 is a group of the formula II 
wherein X2 is a group of the formula CO or OCH2, Q3 is phenyl or 2-pyridyl which optionally bears 1 or 2 substituents selected from fluoro, chloro, bromo, methyl and methoxy, n is 1 and R4 is hydrogen, fluoro, chloro, bromo or methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is a quinazoline derivative of the formula I
wherein X1 is a direct link or a group of the formula NHCO, OCH2 or NHCH2;
Q1 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-oxazolyl, 5-isoxazolyl or 4-imidazolyl which optionally bears a substituent selected from aminomethyl, morpholinomethyl and 2-morpholinoethyl;
m is 1 and R1 is hydrogen or methoxy;
and Q2 is phenyl which optionally bears 1 or 2 substituents selected from fluoro, chloro, bromo and methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
A specific especially preferred compound of the invention is the quinazoline derivative of the formula I:
4-(3-chloro-4-fluoroanilino)-6-(3-furyl)quinazoline, 4-(3-chloro-4-fluoroanilino)-6-(2-thienyl)quinazoline, 4-(3-chloro-4-fluoroanilino)-6-[5-(2-morpholinoethyl)thien-2-yl]quinazoline, 4-(3-chloro-4-fluoroanilino)-6-(5-morpholinomethylthien-3-yl)quinazoline or 4-(3-chloro-4-fluoroanilino)-7-methoxy6-(3-pyridylmethoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is a quinazoline derivative of the formula I
wherein X1 is a direct link;
Q1 is thienyl which bears a substituent selected from amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, pyrrolidin-1-yl-(1-4C)alkyl piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl and 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl;
m is 1 and R1 is hydrogen;
and Q2 is phenyl which optionally bears up to 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl;
or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention is a quinazoline derivative of the formula I
wherein X1 is a direct link;
Q1 is 2-thienyl which optionally bears a substituent selected from methyl, aminomethyl, 2-aminoethyl, methylaminomethyl, 2-methylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, piperidinomethyl, 2-piperidinoethyl, morpholinomethyl, 2-morpholinoethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl, 4-methylpiperazin-1-ylmethyl and 2-(4-methylpiperazin-1-yl)ethyl;
m is 1 and R1 is hydrogen or methoxy;
and Q2 is phenyl which optionally bears 1, 2 or 3 substituents selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl and methoxy;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is a quinazoline derivative of the formula I
wherein X1 is a direct link;
Q1 is 2-thienyl which optionally bears a substituent selected from aminomethyl, morpholinomethyl and 2-morpholinoethyl;
m is 1 and R1 is hydrogen or methoxy;
and Q2 is phenyl which optionally bears 1 or 2 substituents selected from fluoro, chloro, bromo and methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific especially preferred compound of the invention is the quinazoline derivative of the formula I:
4-(3-chloro-4-fluoroanilino)-6-[5-(2-morpholinoethyl)thien-2-yl]quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is a quinazoline derivative of the formula I wherein X1 is a direct link or a group of the formula O;
Q1 is phenyl which optionally bears 1 or 2 substituents selected from fluoro, chloro, bromo, amino, cyano, nitro, aminomethyl, methylaminomethyl, dimethylaminomethyl, diethylaminomethyl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-methylpiperazin-1-ylmethyl;
m is 1 and R1 is hydrogen or methoxy; and
Q2 is phenyl which optionally bears 1, 2 or 3 substituents selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl and methoxy,
or Q2 is a group of the formula II 
wherein X2 is a group of the formula OCH2, Q3 is 2-pyridyl, n is 1 and R4 is hydrogen, fluoro, chloro or methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is a quinazoline derivative of the formula I wherein X1 is a direct link or a group of the formula O;
Q1 is phenyl which optionally bears 1 or 2 substituents selected from amino, aminomethyl, diethylaminomethyl, pyrrolidin-1-ylmethyl, piperidinomethyl and morpholinomethyl;
m is 1 and R1 is hydrogen; and
Q2 is phenyl which optionally bears 1 or 2 substituents selected from fluoro, chloro and methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific especially preferred compound of the invention is the quinazoline derivative of the formula I:
4-(3-methylanilino)-6-phenylquinazoline, 6-(4-aminomethylphenyl)-4-(3-chloro-4-fluoroanilino)quinazoline, 6-(4-aminophenoxy)-4-(3-chloro-4-fluoroanilino)quinazoline, 6-(4-aminomethylphenoxy)-4-(3-chloro-4-fluoroanilino)quinazoline or 4-(3-chloro-4-fluoroanilino)-6-(4-morpholinomethylphenoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Suitable processes include, for example, those illustrated in European Patent Applications Nos. 0520722, 0566226, 0602851, 0635507 and 0635498, and International Patent Applications WO 96/15118 and WO 96/16960. Such processes, when used to prepare a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, are provided as a further feature of the invention and are illustrated by the following representative examples in which, unless otherwise stated, X1, Q1, m, R1 and Q2 have any of the meanings defined hereinbefore for a quinazoline derivative of the formula I. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
(a) The reaction, conveniently in the presence of a suitable base, of a quinazoline of the formula III 
wherein Z is a displaceable group, with an aniline of the formula Q2xe2x80x94NH2.
A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal hydride, for example sodium hydride.
A suitable displaceable group Z is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group. The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alkanol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide. The reaction is conveniently carried out at a temperature in the range, for example, 10 to 250xc2x0 C., preferably in the range 40 to 80xc2x0 C.
The quinazoline derivative of the formula I may be obtained from this process in the form of the free base or alternatively it may be obtained in the form of a salt with the acid of the formula Hxe2x80x94Z wherein Z has the meaning defined hereinbefore. When it is desired to obtain the free base from the salt, the salt may be treated with a suitable base, for example, an organic amine base such as, for example, pyridine. 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
(b) For the preparation of those compounds of the formula I wherein X1 is a direct link, the reaction, conveniently in the presence of a suitable catalyst, of a quinazoline of the formula IV 
wherein Z is a displaceable group as defined hereinbefore, with an organoboron reagent of the formula Q1xe2x80x94B(L1)(L2) wherein each L1 and L2, which may be the same or different, is a suitable ligand.
A suitable value for the ligands L1 and L2 which are present on the boron atom include, for example, a hydroxy, (1-4C)alkoxy or (1-6C)alkyl ligand, for example a hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methyl, ethyl, propyl, isopropyl or butyl ligand. Alternatively the ligands L1 and L2 may be linked such that, together with the boron atom to which they are attached, they form a ring. For example, L1 and L2 together may define an oxy-(2-4C)alkylene-oxy group, for example an oxyethyleneoxy or oxytrimethyleneoxy group such that, together with the boron atom to which they are attached, they form a cyclic boronic acid ester group. Particularly suitable organoboron reagents include, for example, compounds of the formulae Q1xe2x80x94B(OH)2, Q1xe2x80x94B(OPri)2 and Q1xe2x80x94B(Et)2.
A suitable catalyst for the reaction includes, for example, a metallic catalyst such as a palladium(0), palladium(II), nickel(0) or nickel(II) catalyst, for example tetrakis(triphenylphosphine)palladium(0), palladium(II) chloride, palladium(II) bromide, bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)nickel(0), nickel(II) chloride, nickel(II) bromide or bis(triphenylphosphine)nickel(II) chloride. In addition a free radical initiator may conveniently be added, for example an azo compound such as azo(bisisobutyronitrile).
The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran, 1,4-dioxan or 1,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol, and the reaction is conveniently carried out at a temperature in the range, for example 10 to 250xc2x0 C., preferably in the range 60 to 120xc2x0 C.
Organoboron reagents of the formula Q1xe2x80x94B(L1)(L2) may be obtained by standard procedures of organic chemistry which are within the ordinary skill of an organic chemist, for example by the reaction of an organometallic compound of the formula Q1xe2x80x94M, wherein M is, for example, lithium or the magnesium halide portion of a Grignard reagent, with an organoboron compound of the formula Zxe2x80x94B(L1)(L2) wherein Z is a displaceable group as defined hereinbefore. Preferably the compound of the formula Zxe2x80x94B(L1)(L2) is, for example, boric acid or a tri-(1-4C)alkyl borate such as tri-isopropyl borate.
In an alternative procedure the organoboron compound of the formula Q1xe2x80x94B(L1)(L2) may be replaced with an organometallic compound of the formula Q1xe2x80x94M wherein M is a metal atom or a metallic group (i.e. a metal atom bearing suitable ligands). Suitable values for the metal atom include, for example, lithium and copper. Suitable values for the metallic group include, for example, groups which contain a tin, silicon, zirconium, aluminium, magnesium or mercury atom. Suitable ligands within such a metallic group include, for example, hydroxy groups, (1-6C)alkyl groups such as methyl, ethyl, propyl, isopropyl and butyl groups, halogeno groups such as chloro, bromo and iodo groups, and (1-6C)alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy and butoxy groups. A particular organometallic compound of the formula Q1xe2x80x94M is, for example, an organotin compound such as a compound of the formula Q1xe2x80x94SnBu3, an organosilicon compound such as a compound of the formula Q1xe2x80x94Si(Me)F2, an organozirconium compound such as a compound of the formula Q1xe2x80x94ZrCl3, an organoaluminium compound such as a compound of the formula Q1-AlEt2, an organomagnesium compound such as a compound of the formula Q1xe2x80x94MgBr, or an organomercury compound such as a compound of the formula Q1xe2x80x94HgBr.
(c) For the preparation of those compounds of the formula I wherein X1 is a direct link, the reaction, conveniently in the presence of a suitable catalyst as defined hereinbefore, of a quinazoline of the formula V 
wherein each of L1 and L2, which may be the same or different, is a suitable ligand as defined hereinbefore, with a compound of the formula Q1xe2x80x94Z wherein Z is a displaceable group as defined hereinbefore.
The reaction is conveniently carried out in a suitable inert solvent or diluent and at a suitable temperature in an analogous manner to the conditions described in paragraph (b) hereinbefore.
The quinazoline of the formula V may conveniently be obtained by analogous procedures to those described hereinbefore for the preparation of the organoboron reagent of the formula Q1xe2x80x94B(L1)(L2).
(d) For the production of those compounds of the formula I wherein X1 is a group of the formula N(R2)CO or N(R2)SO2, the acylation of an amine of the formula VI 
with a carboxylic acid of the formula Q1xe2x80x94CO2H, or a reactive derivative thereof, or a sulphonic acid of the formula Q1xe2x80x94SO2OH, or a reactive derivative thereof, as appropriate.
A suitable reactive derivative of a carboxylic acid of the formula Q1xe2x80x94CO2H is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol, an ester such as pentafluorophenyl trifluoroacetate or an alcohol such as methanol, ethanol, isopropanol, butanol or N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodiimide such as dicyclohexylcarbodiimide. Analogously suitable reactive derivatives of the sulphonic acid of the formula Q1xe2x80x94SO2OH may be obtained.
The reaction is conveniently carried out in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0 to 120xc2x0 C., preferably at or near ambient temperature.
(e) For the production of those compounds of the formula I wherein X1 is a group of the formula OC(R2)2, SC(R2)2 or N(R2)C(R2)2, the alkylation, conveniently in the presence of a suitable base as defined hereinbefore, of an appropriate phenol, thiophenol or aniline with an alkylating agent of the formula Zxe2x80x94C(R2)2xe2x80x94Q1 wherein Z is a displaceable group as defined hereinbefore.
The reaction is conveniently carried out in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 150xc2x0 C., preferably at or near 80xc2x0 C.
(f) For the production of those compound of the formula I wherein X1 is a group of the formula C(R2)2O, C(R2)2S or C(R2)2N(R2), the alkylation, conveniently in the presence of a suitable base as defined hereinbefore, of the appropriate phenol of the formula HOxe2x80x94Q1, thiophenol of the formula HSxe2x80x94Q1 or aniline of the formula R2NHxe2x80x94Q1, with an alkylating agent of the formula VII 
wherein Z is a displaceable group as defined hereinbefore.
The reaction is conveniently carried out in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0 to 150xc2x0 C., preferably in the range 20 to 70xc2x0 C.
(g) For the production of those compounds of the formula I which possess an aminomethyl substituent or wherein X1 is a group of the formula N(R2)CH2 or CH2N(R2), the reduction of a compound of the formula I which possesses a cyano substituent or wherein X1 is a group of the formula N(R2)CO or CON(R2) as appropriate.
The reduction may be carried out by any of the many procedures known in the art for such transformations. A suitable reducing agent is, for example, an alkali metal aluminium hydride such as lithium aluminium hydride.
The reduction is conveniently carried out in a suitable inert solvent or diluent such as diethyl ether or tetrahydrofuran and at a temperature in the range, for example, 0 to 80xc2x0 C., preferably in the range 15 to 50xc2x0 C.
(h) For the production of those compounds of the formula I which possess an amino substituent, the reduction of a compound of the formula I which possesses a nitro substituent.
The reduction may conveniently be carried out by any of the many procedures known for such a transformation. The reduction may be carried out, for example, by the hydrogenation of a solution of the nitro compound in an inert solvent or diluent as defined hereinbefore in the presence of a suitable metal catalyst such as palladium or platinum. A further suitable reducing agent is, for example, an activated metal such as activated iron (produced by washing iron powder with a dilute solution of an acid such as hydrochloric acid). Thus, for example, the reduction may be carried out by heating a mixture of the nitro compound and the activated metal in a suitable solvent or diluent such as a mixture of water and an alcohol, for example, methanol or ethanol, to a temperature in the range, for example, 50 to 150xc2x0 C., conveniently at or near 70xc2x0 C.
(i) For the production of those compounds of the formula I wherein X1 is a group of the formula NHCH(R2), the reductive amination of a keto compound of the formula R2xe2x80x94COxe2x80x94Q1 with an amine of the formula VIII 
Any reducing agent known in the art for promoting a reductive amination reaction may be employed. A suitable reducing agent is, for example, a hydride reducting agent, for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride. The reaction is conveniently performed in a suitable inert solvent or diluent, for example tetrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride. The reaction is performed at a temperature in the range, for example, 10 to 80xc2x0 C, conveniently at or near ambient temperature.
(j) For the production of those compounds of the formula I wherein X1 is a group of the formula O, S or N(R2), the coupling, conveniently in the presence of a suitable base as defined hereinbefore, of an appropriate phenol, thiophenol or aniline with a compound of the formula Zxe2x80x94Q1 wherein Z is a displaceable group as defined hereinbefore.
Conveniently the reaction may be performed in the presence of a suitable catalyst, for example a metallic catalyst such as a palladium(0) or copper(I) catalyst, for example tetrakis(triphenylphosphine)palladium(0), cuprous chloride or cuprous bromide.
The coupling reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore, preferably in N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide or acetone, and at a temperature in the range, for example, 10 to 150xc2x0 C., conveniently at or near 100xc2x0 C.
When a pharmaceutically-acceptable salt of a quinazoline derivative of the formula I is required, for example a mono- or di-acid-addition salt, it may be obtained, for example, by reaction of said compound with, for example, a suitable acid using a conventional procedure.
As stated hereinbefore the quinazoline derivative defined in the present invention possesses anti-proliferative activity such as anti-cancer activity which is believed to arise from the Class I receptor tyrosine kinase inhibitory activity of the compound. These properties may be assessed, for example, using one or more of the procedures set out below:
(a) An in vitro assay which determines the ability of a test compound to inhibit the enzyme EGF receptor tyrosine kinase. Receptor tyrosine kinase was obtained in partially purified form from A431 cells (derived from human vulval carcinoma) by the procedures described below which are related to those described by Carpenter et al., J. Biol. Chem., 1979, 254, 4884, Cohen et al., J. Biol Chem., 1982, 257, 1523 and by Braun et al., J. Biol. Chem., 1984, 259, 2051.
A-431 cells were grown to confluence using Dulbecco""s modified Eagle""s medium DMEM) containing 5% fetal calf serum (FCS). The obtained cells were homogenised in a hypotonic borate/EDTA buffer at pH 10.1. The homogenate was centrifuged at 400 g for 10 minutes at 0-4xc2x0 C. The supernatant was centrifuged at 25,000 g for 30 minutes at 0-4xc2x0 C. The pelleted material was suspended in 30 mM Hepes buffer at pH 7.4 containing 5% glycerol, 4 mM benzamidine and 1% Triton X-100, stirred for 1 hour at 0-4xc2x0 C., and recentrifuged at 100,000 g for 1 hour at 0-4xc2x0 C. The supernatant, containing solubilised receptor tyrosine kinase, was stored in liquid nitrogen.
For test purposes 40 xcexcl of the enzyme solution so obtained was added to a mixture of 400 xcexcl of a mixture of 150 mM Hepes buffer at pH 7.4, 500 xcexcM sodium orthovanadate, 0.1% Triton X-100, 10% glycerol, 200 xcexcl water, 80 xcexcl of 25 mM DTT and 80 xcexcl of a mixture of 12.5 mM manganese chloride, 125 mM magnesium chloride and distilled water. There was thus obtained the test enzyme solution.
Each test compound was dissolved in dimethylsulphoxide (DMSO) to give a 50 mM solution which was diluted with 40 mM Hepes buffer containing 0.1% Triton X-100, 10% glycerol and 10% DMSO to give a 500 xcexcM solution. Equal volumes of this solution and a solution of epidermal growth factor (EGF; 20 xcexcg/ml) were mixed.
[xcex3-32P]ATP (3000 Ci/mM, 250 xcexcCi) was diluted to a volume of 2 ml by the addition of a solution of ATP (100 xcexcM) in distilled water. An equal volume of a 4 mg/ml solution of the peptide Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly in a mixture of 40 mM Hepes buffer at pH 7.4, 0.1% Triton X-100 and 10% glycerol was added.
The test compound/EGF mixture solution (5 xcexcl) was added to the test enzyme solution (10 xcexcl) and the mixture was incubated at 0-4xc2x0 C. for 30 minutes. The ATP/peptide mixture (10 xcexcl) was added and the mixture was incubated at 25xc2x0 C. for 10 minutes. The phosphorylation reaction was terminated by the addition of 5% trichloroacetic acid (40 xcexcl) and bovine serum albumin (BSA; 1 mg/ml, 5 xcexcl). The mixture was allowed to stand at 4xc2x0 C. for 30 minutes and then centrifuged. An aliquot (40 xcexcl) of the supernatant was placed onto a strip of Whatman p 81 phosphocellulose paper. The strip was washed in 75 mM phosphoric acid (4xc3x9710 ml) and blotted dry. Radioactivity present in the filter paper was measured using a liquid scintillation counter (Sequence A). The reaction sequence was repeated in the absence of the EGF (Sequence B) and again in the absence of the test compound (Sequence C).
Receptor tyrosine kinase inhibition was calculated as follows:       %    ⁢          xe2x80x83        ⁢    Inhibition    =                    100        -                  (                      A            -            B                    )                            C        -        B              xc3x97    100  
The extent of inhibition was then determined at a range of concentrations of test compound to give an IC50 value.
(b) An in vitro assay which determines the ability of a test compound to inhibit the EGF-stimulated growth of the human naso-pharyngeal cancer cell line KB.
KB cells were seeded into wells at a density of 1xc3x97104-1.5xc3x97104 cells per well and grown for 24 hours in DMEM supplemented with 5% FCS (charcoal-stripped). Cell growth was determined after incubation for 3 days by the extent of metabolism of MTT tetrazolium dye to furnish a bluish colour. Cell growth was then determined in the presence of EGF (10 ng/ml) or in the presence of EGF (10 ng/ml) and a test compound at a range of concentrations. An IC50 value could then be calculated.
(c) An in vivo assay in a group of male rats which determines the ability of a test compound (usually administered orally as a ball-milled suspension in 0.5% polysorbate) to inhibit the stimulation of liver hepatocyte growth caused by the administration of the growth factor TGFxcex1 (400 xcexcg/kg subcutaneously, usually dosed twice, 3 and 7 hours respectively after the administration of the test compound).
In a control group of rats, the administration of TGFxcex1 causes on average a 5-fold stimulation of liver hepatocyte growth.
Cell-growth in the control and test animals is determined as follows:
On the morning of the day after the dosing of the test compound (or 0.5% polysorbate in the control group), the animals are dosed with bromodeoxyuridine (BrdU; 100 mg/kg intraperitoneally). The animals are killed four hours later and the livers are excised. Slices are cut from each liver and the uptake of BrdU is determined by a conventional immunohistochemical technique similar to that described on pages 267 and 268 of an article by Goldsworthy et al. in Chemically Induced Cell Proliferation: Implications for Risk Assessment, Wiley-Liss Inc., 1991, pages 253-284. Further tests were carried out using a range of doses of the test compounds to allow the calculation of an approximate ED50 value for the inhibition of liver hepatocyte proliferation as determined by inhibition of the uptake of BrdU.
(d) An in-vivo assay in a group of athymic nude mice (strain ONU:Alpk) which determines the ability of a test compound (usually administered orally as a ball-milled suspension in 0.5% polysorbate) to inhibit the growth of xenografts of the human vulval epidermoid carcinoma cell line A-431.
A-431 cells were maintained in culture in DMEM supplemented with 5% FCS and 2 mM glutamine. Freshly cultured cells were harvested by trypsinization and injected subcutaneously (10 million cells/0.1 ml/mouse) into both flanks of a number of donor nude mice. When sufficient tumour material was available (after approximately 9 to 14 days), fragments of tumour tissue were transplanted into the flanks of recipient nude mice (test day 0). Generally, on the seventh day after transplantation (test day 7) groups of 7 to 10 mice with similar-sized tumours were selected and dosing of the test compound was commenced. Once-daily dosing of test compound was continued for a total of 13 days (test days 7 to 19 inclusive). In some studies the dosing of the test compound was continued beyond test day 19, for example to test day 26. In each case, on the following day the animals were killed and final tumour volume was calculated from measurements of the length and width of the tumours. Results were calculated as a percentage inhibition of tumour volume relative to untreated controls.
Although the pharmacological properties of the compounds of the formula I vary with structural change as expected, in general activity possessed by compounds of the formula I may be demonstrated at the following concentrations or doses in one or more of the above tests (a), (b), (c) and (d):
Test (a): IC50 in the range, for example, 0.01-1 xcexcM;
Test (b): IC50 in the range, for example, 0.1-10 xcexcM;
Test (c): ED50 in the range, for example, 1-100 mg/kg;
Test (d): 20 to 70% inhibition of tumour volume from a daily dose in the range, for example, 50 to 400 mg/kg.
Thus, by way of example, the compound 4-(3-chloro-4-fluoroanilino)-6-[5-(2-morpholinoethyl)thien-2-yl]quinazoline has an IC50 of 0.04 xcexcM in Test (a), an IC50 of 0.19 xcexcM in Test (b) and gives 64% inhibition in Test (d) at a dosage of 50 mg/kglday.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
In general the above compositions may be prepared in a conventional manner using conventional excipients.
The quinazoline derivative will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body area of the animal, i.e. approximately 0.1-100 mg/kg, and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient. Preferably a daily dose in the range of 1-100 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
According to a further aspect of the present invention there is provided a quinazoline derivative of the formula I as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
We have now found that the compounds of the present invention possess anti-proliferative properties which are believed to arise from their Class I (EGF type) receptor tyrosine kinase inhibitory activity. Accordingly the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by Class I receptor tyrosine kinase enzymes, i.e. the compounds may be used to produce a Class I receptor tyrosine kinase inhibitory effect in a warm-blooded animal in need of such treatment. Thus the compounds of the present invention provide a method for treating the proliferation of malignant cells characterised by inhibition of Class I receptor tyrosine kinase enzymes, i.e. the compounds may be used to produce an anti-proliferative effect mediated alone or in part by the inhibition of Class I receptor tyrosine kinase. Accordingly the compounds of the present invention are expected to be useful in the treatment of cancer by providing an anti-proliferative effect, particularly in the treatment of Class I receptor tyrosine kinase sensitive cancers such as cancers of the by lung, colon, rectum, stomach. prostate, bladder, pancreas and ovary. The compounds of the present invention are also expected to be useful in the treatment of other cell-proliferation diseases such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis.
Thus according to this aspect of the invention there is provided the use of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is provided a method for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative as defined immediately above.
As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular cell-proliferation disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. A unit dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged.
The anti-proliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the quinazoline derivative of the invention, conventional radiotherapy or one or more other anti-tumour substances, for example cytotoxic or cytostatic anti-tumour substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine, vindesine and vinorelbine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; antimetabolites, for example 5-fluorouracil, tegafur, methotrexate, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European Patent Application No. 239362 such as N-{5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl}-L-glutamic acid; intercalating antibiotics, for example adriamycin, mitomycin and bleomycin; enzymes, for example asparaginase; topoisomerase inhibitors, for example etoposide and camptothecin; biological response modifiers, for example interferon; and anti-hormones, for example antioestrogens such as tamoxifen, for example antiandrogens such as 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)propionanilide or, for example LHRH antagonists or LHRH agonists such as goserelin, leuprorelin or buserelin and hormone synthesis inhibitors, for example aromatase inhibitors such as those disclosed in European Patent Application No. 0296749, for example 2,2xe2x80x2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-methylpropionitrile), and, for example, inhibitors of 5xcex1-reductase such as 17xcex2-(N-tert-butylcarbamoyl)-4-aza-5xcex1-androst-1-en-3-one. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. According to this aspect of the invention there is provided a pharmaceutical product comprising a quinazoline derivative of the formula I as defined hereinbefore and an additional anti-tumour substance as defined hereinbefore for the conjoint treatment of cancer.
As stated above the quinazoline derivative defined in the present invention is an effective anti-cancer agent, which property is believed to arise from its Class I (EGF type) receptor tyrosine kinase inhibitory properties. Such a quinazoline derivative of the invention is expected to possess a wide range of anti-cancer properties as Class I receptor tyrosine kinases have been implicated in many common human cancers such as leukaemia and breast, lung, colon, rectal, stomach, prostate, bladder, pancreas and ovarian cancer. Thus it is expected that a quinazoline derivative of the invention will possess anti-cancer activity against these cancers. It is in addition expected that a quinazoline derivative of the present invention will possess activity against a range of leukaemias, lymphoid malignancies and solid tumours such as carcinomas and sarcomas in tissues such as the liver, kidney, prostate and pancreas.
It is further expected that a quinazoline derivative of the present invention will possess activity against other cell-proliferation diseases such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis.
It is also to be expected that a quinazoline derivative of the invention will be useful in the treatment of additional disorders of cellular growth in which aberrant cell signalling by way of receptor tyrosine kinase enzymes, including as yet unidentified receptor tyrosine kinase enzymes, are involved. Such disorders include,for example, inflammation, angiogenesis, vascular restenosis, immunological disorders, pancreatitis, kidney disease and blastocyte maturation and implantation.
The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:
(i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration;
(ii) operations were carried out at ambient temperature, that is in the range 18-25xc2x0 C. and under an atmosphere of an inert gas such as argon;
(iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, Germany;
(iv) yields are given for illustration only and are not necessarily the maximum attainable;
(v) melting points were determined using a Mettler SP62 automatic melting point apparatus, an oil-bath apparatus or a Koffler hot plate apparatus.
(vi) the structures of the end-products of the formula I were confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques; proton magnetic resonance chemical shift values were measured on the delta scale and peak multilicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet, unless otherwise stated end-products of the formula I were dissolved in CD3SOCD3 for the determination of NMR values.
(vii) intermediates were not generally fully characterised and purity was assessed by thin layer chromatography (TLC), infra-red (IR) or NMR analysis;
(viii) the following abbreviations have been used:
DMF N,N-dimethylformamide;
DMA N,N-dimethylacetamide;
NMP N-methylpyrrolidin-2-one;
THF tetrahydrofuran;
DME 1,2-dimethoxyethane.